Significance: This proposal is for a type 2 hybrid effectiveness-implementation trial to test an intervention and implementation strategy of a peer-delivered, stepped care approach for integrating HIV and substance use (SU) services in a resource-limited primary care setting. Globally, a SU treatment gap exists, with only 1-4% of individuals who need treatment in the most resource-limited contexts receiving minimally adequate treatment. Given the impact of untreated SU on poor HIV outcomes along the care continuum, efforts are needed to sustainably integrate behavioral interventions into primary care settings to reach individuals at highest risk for poor ART adherence and SU outcomes. This gap in care in resource-limited settings will be met through implementing a peer-delivered, stepped care intervention, which has been successfully piloted in Cape Town, South Africa in the PI’s K23 award (“Khanya”). Preliminary work: Our team has developed and adapted the Khanya peer-delivered intervention based on key stakeholder feedback to improve ART adherence among PLWH with SU in primary care in South Africa. Khanya integrates Life-Steps, a single-session problem solving and motivational intervention for ART adherence, with brief behavioral skills to reduce SU (i.e., behavioral activation, mindfulness, relapse prevention). The PI’s K23 award included a pilot Type 1 hybrid effectiveness- implementation trial that demonstrated initial feasibility, acceptability, and preliminary effectiveness of Khanya for improving ART adherence compared to enhanced standard of care (ESOC). At post-treatment, adherence in Khanya was M=60.3% days vs. M=26.5% in ESOC. Methods: Guided by RE-AIM, the current study aims to test in a Type 2 hybrid effectiveness-implementation trial the effectiveness and implementation of a stepped- care Khanya intervention for PLWH at highest risk for ongoing ART nonadherence and HIV transmission. A stepped care approach is appealing in a resource-limited context, as the least resource intensive part of an intervention is delivered first, and only individuals who do not respond receive the more resource intensive part of the intervention. 150 PLWH with SU will be recruited from an integrated primary care site and randomized to ESOC (i.e., facilitated referral to public SU treatment) or Khanya. Khanya begins with Life-Steps + ESOC, and only those who continue to demonstrate ART nonadherence (i.e., detected using real-time electronic adherence monitoring; ≥3 missed doses in a 2-week period) will step up to receive the full intervention. Based on our pilot data, we anticipate Life-Steps + ESOC alone will be sufficient for ~44% of patients to overcome barriers to ART adherence, but the other ~56%, particularly those with more severe SU, will require the full intervention. Participants will be followed for 12 months on: ART adherence (Wisepill, DBS concentrations, and self-report), SU (urinalysis, PEth, and self-report), implementation (reach and upta...